The phytogenic fungus Pyrenophora teres has been a source of a number of fungal metabolites of interesting and varying biological activities. These metabolites include the pyrenolides A ± C, [1] simple macrocyclic lactones that exhibit potent growth-inhibitory and morphogenic activities toward fungi. A fourth metabolite, pyrenolide D (1), [2] is structurally distinct from the other members of this family in that it incorporates a highly oxygenated tricyclic spiro-g-lactone structure related to certain members of the cephalosporolide class of natural products. [3] Moreover, pyrenolide D is further distinguished from the other pyrenolides in that it is not active toward fungi, but rather that it exhibits significant cytotoxic activity toward HL-60 cells. This biological profile, in combination with its densely functionalized polycyclic structure, spawned our efforts to develop a synthetic approach to 1 that would also establish the absolute configuration of the natural product. We report herein the first total synthesis of 1 by a very short sequence. In this context, a method for the efficient con-struction of highly oxygenated tetrahydrofurans from glycal starting materials is reported.Initial retrosynthetic disconnection of 1 (Scheme 1) leads back to a 2-alkoxyfuran 2 and the highly oxygenated tetrahydrofurfural derivative 3 as viable synthetic precursors. Scheme 1. Retrosynthetic analysis.Although a number of synthetic strategies to prepare 3 can be envisioned through the synthesis and cyclization of acyclic polyol precursors, we reasoned that a more efficient approach might arise from a stereoselective oxidative ring contraction of a glycal substrate such as 6-deoxy-d-gulal (4), incorporating three of the four stereocenters within 3. For such an oxidative ring contraction process to be feasible, an appropriate electrophilic oxidant 6 (Scheme 2) is required. Not only must Scheme 2. Oxidative ring contraction of glycals. this reagent efficiently perform an electrophilic activation of the glycal substrate (5 37), but it must also concomitantly install a potent leaving group at the C2 position of the activated pyranoside intermediate 7. This would hopefully allow 1,2-migration of the endocyclic CÀO bond in a displacement of the C2 leaving group, resulting in a net oxidative ring contraction of the glycal substrate to form the C-furanoside product 8, an intermediate that directly maps onto the proposed synthetic intermediate 3 (Scheme 1). Given our interest in glycal activation processes, [4] we sought to establish the means to effect the conversion of 5 into 8 as one of the key steps in the synthesis of 1.Based on this strategy, the initial synthetic target involved the preparation of 2,3-di-O-protected-6-deoxy-d-gulal (4) as the desired substrate for the formation of the C-furanoside 3. The synthesis commenced (Scheme 3) with the preparation of the pseudoglycal 10 from commercially available tri-O-acetyld-galactal (9) through a three-step sequence that included: SnCl 4 -catalyzed Ferrier-type glycosylation of thi...
